CCR2-overexpressing biomimetic carrier-free nanoplatform for enhanced cascade ferroptosis tumor therapy

Ferroptosis-based nanoplatforms have shown great potential in cancer therapy. However, they also face issues such as degradation and metabolism. Carrier-free nanoplatforms consisting of active drugs can effectively avoid the security issues associated with additional carrier ingredients. Herein, a biomimetic carrier-free nanoplatform (HESN@CM) was designed to treat cancer by modulating cascade metabolic pathways of ferroptosis. CCR2-overexpressing macrophage membrane-modified HESN can target cancer cells via the CCR2-CCL2 axis. The acidic tumor microenvironment (TME) can disrupt the supramolecular interaction of HESN, releasing hemin and erastin. Then, erastin could induce cancer cells ferroptosis by inhibiting system X_C^- pathways, while hemin, a vital component of blood to transport oxygen, could be broken down by heme oxygenase-1 (HO-1), increasing the intracellular Fe²⁺ concentration to induce cancer cells' ferroptosis further. Meanwhile, erastin could enhance the activity of HO-1, further promoting the release of Fe²⁺ from hemin. As a result, HESN@CM demonstrated superior therapeutic efficacy in both primary and metastatic tumors in vitro and in vivo. The carrier-free HESN@CM provided cascade ferroptosis tumor therapy strategies for potential clinical application. STATEMENT OF SIGNIFICANCE: CCR2-overexpressing biomimetic carrier-free nanoplatform (HESN@CM) was designed for cancer treatment by modulating metabolic pathways of ferroptosis. HESN modified with CCR2-overexpressing macrophage membrane can target tumor cells via the CCR2-CCL2 axis. HESN was composed of hemin and erastin without additional vectors. Erastin could directly induce ferroptosis, while hemin could be broken down by heme oxygenase-1 (HO-1), increasing the intracellular Fe²⁺ concentration to enhance ferroptosis further. Meanwhile, erastin could improve the activity of HO-1, promoting the release of Fe²⁺ from hemin. Therefore, HESN@CM with good bioavailability, stability, and simple preparation can realize cascade ferroptosis tumor therapy and have the potential prospect of clinical translation.